WO2007112574A1

WO2007112574A1 - Extended release composition of venlafaxine

Info

Publication number: WO2007112574A1
Application number: PCT/CA2007/000540
Authority: WO
Inventors: Isa Odidi; Amina Odidi
Original assignee: Isa Odidi; Amina Odidi
Priority date: 2006-04-03
Filing date: 2007-04-03
Publication date: 2007-10-11

Abstract

An extended release composition that comprises a coated compressed core. The coated compressed core has a core and a coating composition. The compressed core comprises at least about 45 wt% of a venlafaxine ingredient; less than about 50 wt% of at least one component that acts as both a diluent and a compression aid; less than about 10 wt% of at least one glidant; and less than about 10 wt% of at least one lubricant. The coating composition comprises at least one water soluble gellable polymer; and at least one water insoluble organosoluble polymer.

Description

EXTENDED RELEASE COMPOSITION OF VENLAFAXINE

FIELD OF THE INVENTION

The present invention relates to an extended release composition. The present invention also relates to its use and method for making the same.

BACKGROUND OF THE INVENTION Many pharmaceutical oral dosage forms for extended release of drugs are based on polymeric matrices. These dosage forms have a tendency to dose dump when taken under feed conditions and produce a burst effect under fasted conditions. This is due to an initial high rate of drug input that may result in untoward effects such as gastrointestinal effects such as nausea, vomiting, dizziness, and headache. Significant differences in pharmacokinetic matrices between fasted and feed states have also been observed for these systems. Many attempts have been made to solve this problem by use of encapsulated coated spheroids made by extrusion spheronization. An example of such an attempt is U.S. Patent No. 6,274,171 which teaches an extended release formulation of venlafaxine hydrochloride comprising a pharmaceutically acceptable capsule containing spheroids made by extrusion spheronization and comprised of from about 6 wt% to about 40 wt% venlafaxine hydrochloride, about 50 wt% to about 94 wt% microcrystalline cellulose and optionally, from about 0.25 wt% to about 1 wt% by weight of hydroxypropyl-methylcellulose, wherein the spheroids are coated with a film coating composition comprised of from about 80 wt% to about 90 wt% of film coating of ethyl cellulose, and from about 10 wt% to about 20wt% by weight of film coating of hydroxypropylmethylcellulose. Products made using venlafaxine hydrochloride still show a high rate of input resulting in side effects such as nausea and vomiting leading to regulatory bodies recommending that they should be administered with food. Apart from this problem, the method of fabricating the products is laborious and results in a high percentage of rejects which have to be reworked. Thus, it has not come as a surprise to see a plethora of prior art teaching alternative approaches to delivering venlafaxine, such as those referenced below.

International Patent Application No. WO 2006/015485 is directed to an extended release capsule comprising venlafaxine hydrochloride wherein part of the drug content is in the form of delayed-release coated spheroids and a second part of the drug content is in a prompt-release form.

International Patent Application No. WO 2006/010605 is directed to a method for the preparation of a pharmaceutical composition containing venlafaxine or a pharmaceutically acceptable salt thereof comprising the steps of (1 ) preparing a dispersion of venlafaxine or a venlafaxine salt in a solvent wherein venlafaxine or the venlafaxine salts has a solubility of less than 25 g/L at room temperature; (2) converting the dispersion of step (1 ) into particulate form; (3) coating the particles obtained in step (2) with a layer of a sustained release polymer. International Patent Application No. WO 2005/112901 is directed to an extended release pharmaceutical composition of venlafaxine hydrochloride comprising a pharmaceutically acceptable capsule containing minitablets. The minitablets comprise from about 20 wt% to about 70 wt% of venlafaxine hydrochloride, polyvinyl acetate, and one or more pharmaceutically acceptable excipients. The minitablets have a diameter from about 1 mm to 5 mm and are coated with a release controlling composition.

International Patent Application No. WO 2005/074895 is directed to an extended release, once daily pharmaceutical formulation comprising venlafaxine hydrochloride and pharmaceutically acceptable excipients. More particularly, it is directed to an extended release composition in the form of mini-tablets, which are incorporated in hard gelatin capsules.

International Patent Application No. WO 2005/053657 is directed to a venlafaxine containing coated tablet with controlled release, which contains venlafaxine, or its salt with an inorganic or carboxylic acid, in amounts from 20 wt% to 60 wt%, and a hydrophilic polymer in amounts from 30 to 70 wt%, based on the weight of the core, in its core, and from 1 to 3 wt% of a water- poorly permeable or impermeable polymer in its coating, and a method of preparation thereof.

International Patent Application No. WO 2005/048923 is directed to a controlled release dosage form of venlafaxine that comprises an immediate release pellet and an extended release pellet.

International Patent Application No. WO 2005/039555 is directed to an extended release tableted dosage formulation of venlafaxine hydrochloride or an optical form thereof and a carboxyvinyl polymer.

International Patent Application No. WO 2005/039527 is directed to an extended release pharmaceutical dosage form for orally delivering drugs to mammals. More particularly, it is directed to dosage forms of water soluble drugs such as venlafaxine, enantiomeric forms of venlafaxine, metabolites of venlafaxine such as O-desmethylvenlafaxine (ODV) or enantiomeric forms of the metabolites. The dosage form has a solid core with a first substance insoluble in gastrointestinal media and a drug dispersed therein and a coating applied to the core. The coating has a second substance insoluble in gastrointestinal media and a component that is soluble in gastrointestinal media.

International Patent Application No. WO 2005/034930 is directed to pellets containing venlafaxine hydrochloride and a process for the preparation thereof. The pellets are nearly spherical in shape and comprise pharmaceutically active venlafaxine hydrochloride in an amount of at most 80 wt%, 10 to 60 wt% sodium chloride and/or potassium chloride, 10 to 60 wt% of microcrystalline cellulose and optionally, other pharmaceutically acceptable excipients and/or peptization promoting additives.

International Patent Application No. WO 2005/013954 is directed to a modified release tablet of venlafaxine hydrochloride is formed by a core containing a lipophilic matrix and venlafaxine hydrochloride and a water- insoluble, permeable coating thereover. International Patent Application No. WO 2005/013953 is directed venlafaxine besylate is formulated into an extended release tablet using a coating that contains ammonio methacrylate copolymer(s). International Patent Application No. WO 2005/009414 is directed to a hard gelatin capsule containing mini tablets having a core containing 10 to 40 wt% venlafaxine hydrochloride, 40 to 80 wt% gelling agent, 30 to 90 wt% of a non-swellable agent and a conjugation agent, a surfactant or a polymer, and excipients; and a coating layer.

International Patent Application No. WO 2004/108117 is directed to an extended release osmo-microsealed formulation comprising an inner solid osmo-microsealed particulate phase consisting of a therapeutically effective amount of venlafaxine Active or salt and at least one osmogen/osmotic agent or osmo polymer, a diluent, a binder and a hydrophobic membrane forming the core and an outer solid continuous phase consisting of hydrophilic water soluble and/or swellable polymer, compressed into tablets.

International Patent Application No. WO 2004/096186 is directed to an extended release formulation for administration of venlafaxine in an oral tablet dosage form. The formulation has a core in the form of a tablet, over which an outer coating is layered. The core contains venlafaxine, at least 40 wt% of a filler, and at least 5 wt% of a water soluble cellulosic polymer, and at least 5 wt% of ethyl cellulose. The core is coated with a coating material. The coating contains a mixture of water soluble cellulosic polymer and a water insoluble cellulosic polymer. The amount of velafaxine used is typically 22 wt% to 24 wt%.

International Patent Application No. WO 2004/091580 relates to coated pellets comprising a) a pellet core which comprises venlafaxine hydrochloride; b) a first coating which comprises a lipophilic layer (e.g fat, fatty alcohol or wax) or a sparingly water-soluble layer (e.g. sugar), and c) a second coating which comprises a water-insoluble polymer or polymer mixture.

International Patent Application No. WO 2004/047718 is directed to a process for the manufacture of a pharmaceutical composition comprising an inert core and a coating of up to about 70 wt% of venlafaxine or its pharmaceutical acceptable salt, binder, and an antitack agent.

International Patent Application No. WO 2004/037226 is directed to a delayed burst release formulation comprising a core formed as a compressed tablet and an outer coating that surrounds the core. The core comprises venlafaxine, or a pharmaceutically acceptable salt thereof, at least one burst controlling agent and a disintegrant and the outer coating comprises a water insoluble hydrophobic carrier and water-insoluble but hydrophilic particulate matter.

International Patent Application No. WO 2003/082261 is directed to a pharmaceutical composition comprising venlafaxine hydrochloride and sodium carboxymethyl cellulose.

International Patent Application No. WO 2003/055475 is directed to a solid controlled release pharmaceutical formulation that comprises a core comprising venlafaxine, polyvinylpyrrolidone, a low viscosity hydrophilic polymer and a high viscosity hydrophilic polymer; and a polymeric coating comprising a water high permeable polymer and a water low permeable polymer. International Patent Application No. WO 2003/041692 is directed to an extended release composition comprising venlafaxine hydrochloride, in which Venlafaxine Hydrochloride is coated on an inert core, which coated core is then coated with a polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride. International Patent Application No. WO 2002/102129 is directed to a process for the preparation of a formulation comprising coating inert spherical cores with venlafaxine hydrochloride.

International Patent Application No. WO 2002/17889 is directed to a transdermal therapeutic system in the form of a plaster, for administering the active agent venlafaxine.

International Patent Application No. WO 2001/51041 is directed an osmotic device containing controlled release venlafaxine in the core in combination with an anti-psychotic agent in a rapid release external coat. International Patent Application No. WO 99/22724 is directed to a spheroid core, free of hydroxypropylmethylcellulose comprising venlafaxine hydrochloride and microcrystalline cellulose. The core can contain a coating of ethylcellulose and hydroxypropylmethylcellulose. Attempts to use a higher concentration of venlafaxine in a compressed tablet have not been achieved. It has been found that compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. It has been reported that the tablets prepared as hydrogel sustained release formulations typically gave 40- 50% dissolution at 2 hrs, 60-70% dissolution at 4 hrs and 85-100% dissolution at 8 hrs.

There is still a need, however, for an extended release composition of venlafaxine incorporating higher concentrations of venlafaxine and methods for producing the same.

SUMMARY OF THE INVENTION

In accordance with an aspect, there is provided an extended release composition comprising a coated compressed core having a core and a coating composition, (i) the compressed core comprising: at least about 45 wt% of a venlafaxine ingredient; less than about 50 wt% of at least one component that acts as both a diluent and a compression aid; less than about 10 wt% of at least one glidant; and less than about 10 wt% of at least one lubricant; and (ii) the coating composition comprising: at least one water soluble gellable polymer; and at least one water insoluble organosoluble polymer.

In accordance with another aspect, there is provided a method for administering the extended release composition to a mammal in need of treatment for depression, panic disorder, anxiety disorder and/or social phobias.

In accordance with yet another aspect, there is provided a use of the extended release composition in a medicament for the treatment of depression, panic disorder, anxiety disorder and/or social phobias.

In accordance with another aspect, there is provided a use of the extended release composition for the treatment of depression, panic disorder, anxiety disorder and/or social phobias. In accordance with another aspect, there is provided a method for making the extended release composition, the method comprising: combining the venlafaxine ingredient, said at least one component, and said at least one glidant and granulating in a solvent to provide granules; combining the granules with said at least one lubricant to provide lubricated granules; compressing said lubricated granules into the core; and coating the core with the coating composition.

The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

Certain embodiments of the present invention will now be described more fully with reference to the accompanying drawings: Figure 1 is a plasma concentration profile for venlafaxine HCI (fed condition) based on a 150 mg capsule formulation made using Example 1 described herein in comparison to the spheroid composition of U.S. Patent

No. 6,274,171 ; and

Figure 2 is a plasma concentration profile for O-Desmethylvenlafaxine (fed condition) based on a 150 mg capsule formulation made using Example 1 described herein in comparison to the spheroid composition of U.S. Patent

No. 6,274,171.

DETAILED DESCRIPTION OF THE INVENTION The term "venlafaxine ingredient" referred to herein encompasses at least one of venlafaxine, a base of venlafaxine, a polymorph of venlafaxine, a derivative of venlafaxine, a metabolite of venlafaxine, an enantiomeric form of venlafaxine, an enantiomeric form of the base of venlafaxine, an enantiomeric form of the polymorph of venlafaxine, an enantiomeric form of the derivative of venlafaxine, an enantiomeric form of the metabolite of venlafaxine, a pharmaceutically acceptable salt of the venlafaxine, a pharmaceutically acceptable salt of the base of venlafaxine, a pharmaceutically acceptable salt of the polymorph of venlafaxine, a pharmaceutically acceptable salt of the derivative of venlafaxine, a pharmaceutically acceptable salt of the metabolite of venlafaxine, a pharmaceutically acceptable salt of the enantiomeric form of venlafaxine, a pharmaceutically acceptable salt of the enantiomeric form of the base of venlafaxine, a pharmaceutically acceptable salt of the enantiomeric form of the polymorph of venlafaxine, a pharmaceutically acceptable salt of the enantiomeric form of the derivative of venlafaxine, and/or a pharmaceutically acceptable salt of the enantiomeric form of the metabolite of venlafaxine. Examples of some metabolites of venlafaxine include O- desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV).

The IUPAC name for Venlafaxine is 1-[2-dimethylamino)-1-(4- methoxyphenyl) ethyl] cyclohexanol. This drug is used in the neuropharmacological field for treating depression. The present invention is directed to an extended release composition comprising a venlafaxine ingredient and to a method of using and preparing same in order to control the rate and extent of delivery of the venlafaxine ingredient in mammals.

In general, the extended release composition of the present invention do not have a tendency to (i) dose dump when taken under feed conditions, or (ii) produce a burst effect under fasted conditions. The extended release composition of the present invention may mitigate current incidences of untoward effects such as Gl effects (e.g. nausea, vomiting), dizziness, and headache and does not show significant differences in pharmacokinetic matrices between fasted and feed states.

The extended release composition of the present invention comprises a higher concentration of a venlafaxine ingredient as compared to the prior art. Therefore, a higher amount of the extended release composition would not be necessary in comparison to the prior art formulations of venlafaxine. In addition, it would not be expected that the highly water soluble venlafaxine ingredients would provide an extended release composition, especially a composition comprising a higher concentration of a venlafaxine ingredient in comparison to the prior art. For example, attempts in the prior art to use a venlafaxine ingredient in hydrogel technology proved to be fruitless since the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. It has been reported that the tablets prepared as hydrogel sustained release formulations typically gave 40-50% dissolution at 2 hrs, 60-70% dissolution at 4 hrs and 85-100% dissolution at 8 hrs.

The extended release composition of the present invention has at least about 45 wt% of a venlafaxine ingredient. In an embodiment, the extended release composition comprises a compressed core. The compressed core is coated with a coating composition, providing a coated compressed core. The core has at least about 45 wt% of a venlafaxine ingredient; at least one component that acts as both a diluent and a compression aid; at least one glidant and at least one lubricant. Typically, the core has from about 45 wt% to about 95 wt% of a venlafaxine ingredient; less than about 50 wt% of at least one component that acts as both a diluent and a compression aid; less than about 10 wt% of at least one glidant and less than about 10 wt% of at least one lubricant. The coating composition has at least one water soluble gellable polymer and at least one water insoluble organosoluble polymer. Typically, the coating composition has less than about 60 wt% of at least one water soluble gellable polymer and less than about 75 wt% of at least one water insoluble organosoluble polymer.

In a more specific embodiment regarding the core of the extended release composition, the core has at least about 45 wt% of a venlafaxine ingredient; microcrystalline cellulose, lactose, mannitol, calcium phosphate and/or sorbitol; silicon dioxide; and magnesium stearate, talc and/or glycerol monostearate. More particularly, the core has from about 45 wt% to about 95 wt% of a venlafaxine ingredient; less than about 50 wt% microcrystalline cellulose, lactose, mannitol, calcium phosphate and/or sorbitol; less than about 10 wt% silicon dioxide; and less than about 10 wt% magnesium stearate, talc and/or glycerol monostearate. In a more specific embodiment regarding the coating composition of the extended release composition, the coating composition comprises hydroxypropylmethylcellulose and ethylcellulose. More particularly, the coating composition has less than about 60 wt% hydroxypropylmethylcellulose and less than about 75 wt% ethylcellulose. Further embodiments of the core include:

The venlafaxine ingredient can also be present in the composition of from about 50 wt% to about 95 wt%; about 55 wt% to about 95 wt%; about 60 wt% to about 90 wt%; about 60 wt% to about 80 wt%; or from about 65 wt% to about 80 wt%. The component that acts as both a diluent and a compression aid can also be present in the composition of from about 5 wt% to about 45 wt%; from about 5 wt% to about 35 wt%; from about 10 wt% to about 35 wt%; from about 15 wt% to about 35 wt%; or from about 25 wt% to about 35 wt%. The concentration of this component depends on the type of component used. For example, if the component has more of the diluent characteristic than the compression aid characteristic, a higher percentage of the component may be used in the composition to compensate for the lower compression aid characteristic. Moreover, if a mixture of components are used, their properties may compensate for one another's different properties; possibly offsetting each of the properties of each component.

The glidant can also be present in the composition of from about 0.5 wt% to about 5 wt%; from about 0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%. The lubricant can also be present in the composition of from about 0.5 wt% to about 5 wt%; from about 0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%.

Further embodiments of the coating composition include: The water soluble gellable polymer can also be present in the coating composition of from about 5 wt% to about 55 wt%; from about 10 wt% to about 55 wt%; from about 15 wt% to about 55 wt%; from about 10 wt% to about 35 wt%; or from about 15 wt% to about 35 wt%.

The water insoluble organosoluble polymer can also be present in the composition of from about 20 wt% to about 73 wt%; from about 35 wt% to about 65 wt%; from about 30 wt% to about 50 wt%; from about 30 wt% to about 45 wt%; or from about 40 wt% to about 50 wt%.

The ratio of the water soluble gellable polymer to the water insoluble organosoluble polymer in the coating can be, typically, from about 24:76 to about 76:24 or from about 30:70 to about 40:60. The weight percentages of the components (e.g. venlafaxine ingredient; the component that acts as both a diluent and a compression aid, the glidant and lubricant) in the core are based upon the total weight of the core. The weight percentages of the components in the coating composition are based upon the total weight of the coating. The coated compressed core may include the following amount of coating:

The core can be coated with of from about 0.1 wt% to about 50 wt% of the coating based on the total weight of the coating and the core of the final product. More typically, the coating is from about 1 wt% to about 20 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 7 wt%, from about 3.5 wt% to about 7 wt%, from about 3.5 wt% to about 6 wt%, or from about 4 wt% to about 5 wt%. The coating is typically applied to the core to yield a surface area of less than about 100 mg/cm². The coating can be one or more layers. Specific embodiments of the extended release composition include:

The core that comprises from about 45 wt% to about 95 wt% of a venlafaxine ingredient; from about 10 wt% to about 30 wt% microcrystalline cellulose; from about 5 wt% to about 20 wt% lactose; less than about 10 wt% of silicon dioxide and less than about 10 wt% magnesium stearate. The core is coated with from about 1.0 wt% to about 20 wt% based on the total weight of the coating and the core of the final product. More typically, the coating is from about 3.5 wt% to about 7 wt%, most typically, at from about 4 wt% to about 5 wt%. The coating composition comprises from about 15 wt% to about 55 wt% of hydroxypropylmethylcellulose and from about 35 wt% to about 73 wt% of ethylcellulose. The core is free of water soluble or water insoluble cellulose ether. In another embodiment, the lactose is replaced with mannitol and/or sorbitol. In yet another embodiment, the microcrystalline cellulose and lactose are replaced by mannitol and/or sorbitol.

In a further embodiment, the extended release composition comprises a core that has from about 60 wt% to about 80 wt% of a venlafaxine ingredient, particularly venlafaxine hydrochloride, from about 10 wt% to about 25 wt% microcrystalline cellulose, from about 5 wt% to about 15 wt% lactose, less than about 10 wt% of silicon dioxide and less than about 10 wt% magnesium stearate. The core has a coating of from about 3 wt% to about 7 wt% percent based on the total weight of the coating and the core. More typically, the extended release composition comprises a core that has about 70 wt% of a venlafaxine ingredient, particularly venlafaxine hydrochloride, from about 15 wt% to about 25 wt% microcrystalline cellulose, from about 10 wt% to about 15 wt% lactose, and from about 0.5 wt% to about 3 wt% silicon dioxide, and from about 0.5 wt% to about 3 wt% magnesium stearate. The core has a coating of from about 0.5 wt% to about 3 wt% based on the total weight of the coating and the core.

With respect to the coating composition, the coating composition may comprise less than about 60 wt% of at least one water soluble gellable polymer and less than about 75 wt% of at least one water insoluble organosoluble polymer. The coating composition can also comprise a plasticizer and an anti-tacking agent. For example, from about 10 wt% to about 80 wt% of at least one anti-tacking agent and about 10 wt% to about 80 wt% of at least one plasticizer can be used to make the coating composition. In a specific embodiment, the coating composition comprises of from about 15 wt% to about 50 wt% of hydroxypropylmethylcellulose and from about 35 wt% to about 65 wt% of ethylcellulose.

The extended release composition of the present invention can be any suitable size for drug delivery. Typically, the coated core weighs less than about 2 grams; from about 5 mg to about 1000 mg; from about 5 mg to about 500 mg; from about 5 mg to about 100 mg; from about 5 mg to about 30 mg; or from about 20 mg to 30 mg. The coated core may have a diameter of less than about 20 mm; from about 1 mm to about 10 mm; from about 1 mm to about 5 mm; or from about 2 mm to about 4 mm and a thickness that is less than about 20 mm; from about 1 mm to about 10 mm; from about 1 mm to about 5 mm; or from about 2 mm to about 4 mm. The coated core may be, for example, a tablet, pellet, mini-tablet, capsule and/or caplet. A plurality of coated cores may be combined and encapsulated in a capsule or made into a tablet or caplet.

With respect to the venlafaxine ingredient, typically the venlafaxine ingredient is venlafaxine and/or at least one pharmaceutically acceptable salt thereof.

Some examples of the component that acts as both a diluent and a compression aid are microcrystalline cellulose, calcium phosphate, mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol; arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, and raffinose. More typically, microcrystalline cellulose, lactose, mannitol, calcium phosphate and/or sorbitol are used.

Some examples of glidant(s) are silicon dioxide, starch, calcium silicate, Cabosil, Syloid, and silicon dioxide aerogels. Typically, silicon dioxide is used. Some examples of lubricant(s) are alkali stearates such as magnesium stearate, calcium stearate, zinc stearate, polyethylene glycol, adipic acid, hydrogenated vegetable oils, sodium chloride, sterotex, glycerol monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil and the like may be employed. Waxy fatty acid esters, such as glyceryl behenate, sold as "Compritol" products, can be used. Other useful commercial lubricants include "Stear-O-Wet" and "Myvatex TL". Typically, magnesium stearate, talc and/or glycerol monostearate.

Additional excipients may be included in the composition of the present invention. Further examples of excipients can include pigments, colorants, flavoring agents, and sweetners. Examples of water soluble gellable polymers include swellable, gellable cellulose ethers, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, copolyvidone, polyvinyl pyrrolidone, polyethylene glycols, and hydroxyethyl cellulose, polyols, carbomers, carboxymethyl cellulose, polysaccharide gums, and polyethylene oxides. Typically, hydroxypropylmethyl cellulose is used. Examples of water insoluble organosoluble polymers include polyvinyl acetate, eudragit, cellulose derivatives such as ethyl cellulose, cellulose acetate and their plasticizers are selected among dibutyl sebacate, triethyl citrate, castor oil, glyceryl monostearate, diethyl phthalate, glyceryl trihepthanoate. Numerous core formulations were prepared using different grades of the component that acts as both a diluent and a compression aid, the glidant and the lubricant and different ratios of a venlafaxine ingredient and the component that acts as both a diluent and a compression aid, the glidant and the lubricant to provide a suitable granulation mix having high drug load in the absence of a binder and that could be formulated into a proper compressed core, for example, a tablet, pellet, mini-tablet, capsule and/or caplet. During the process, compaction issues and difficulty in flowability and granule segregation, stickiness and capping had to be addressed. Addition of the venlafaxine ingredient, the component that acts as both a diluent and a compression aid, the glidant, and the lubricant made production of tablets practical. With respect to the coating composition, the deposition of the coating around the core provided suitable therapeutic end points, a lag time and/or lag phase without the use of an enteric coat, as has been the tradition in the industry. These choices also made the efficient deposition and adhesion of the coat on the compressed core possible and reproducible. The coating composition does not allow for agglomeration of the cores during coating but at the same time allows the coating to adhere to the cores.

Each of the resultant coated cores of the extended release composition can be encapsulated, for example, in pharmaceutically acceptable capsules, such as starch, hydroxypropylmethyl cellulose or gelatin capsules, more particularly, hard gelatin capsules or the coated cores can be combined in a sachet, to form a further tablet, and/or a caplet.

The extended release composition of the present invention can be encapsulated or non-encapsulated to provide, in a single dose, a therapeutic blood serum level over a twelve or twenty four hour period that are capable of demonstrating a lag time and/or lag phase during drug release in-vivo. For example, the extended release composition of the present invention can provide peak serum levels of less than 500 ng/ml and extended therapeutically effective plasma levels over a twelve or twenty four hour period. The extended release composition is also capable of exhibiting a plasma concentration lag time and/or lag phase of less than about 12 hours during drug release in-vivo.

The extended release composition of the present invention can be used for any type of treatment for which the venlafaxine ingredient is suitable. Uses which are known in the art include, but are not limited to, all forms of depression, either in hospital or in out-patient clinics, depressive illness with or without melancholy, depression accompanied by anxiety, depression related to aging, episodes of depression in a limited sense, especially an episode with vital symptoms, major depression, including severe episodes in hospitalized patients, new depressive episodes, panic disorder, generalized anxiety disorder-short or long-term treatment, anxiety, including long-term treatment for melancholia, and social phobias. In an embodiment, there is provided a method for administering the extended release composition of the present invention to a mammal in need of treatment for depression, panic disorder, anxiety disorder and/or social phobias.

One of the methods of the present invention can provide a therapeutic blood plasma concentration of the venlafaxine ingredient over a twelve or twenty four hour period with diminished incidences of nausea and emesis. The method comprises administering orally to a patient in need thereof an extended release composition of the present invention, with or without a lag time, to provide a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours. Another method can provide a therapeutic blood plasma concentration of the venlafaxine ingredient over a twelve or twenty four hour period with diminished incidences of nausea and emesis. The method comprises administering orally to a patient in need thereof an extended release composition of the present invention that after a lag time provides a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

A further method can substantially eliminate the troughs and peaks of drug concentration in a patients blood plasma attributed to the therapeutic metabolism of plural daily doses of the venlafaxine ingredient. The method comprises administering orally to a patient in need thereof, an extended release composition of the present invention, with or without a lag time, to provide a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

Another method can substantially eliminate the troughs and peaks of drug concentration in a patients blood plasma attributed to the therapeutic metabolism of plural daily doses of the venlafaxine ingredient. The method comprises administering orally to a patient in need thereof, an extended release composition of the present invention that after a lag time provides a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

In a further embodiment, the dosage form of the extended release composition of the present invention is capable of exhibiting a plasma concentration lag time of less than 12 hours under feed conditions. In still another embodiment, the dosage form of the extended release composition of the present invention is capable of exhibiting a plasma concentration lag time of less than 12 hours under fasting conditions. Figures 1 and 2 show a plasma concentration profile for venlafaxine and O-desmethylvenlafaxine under fed conditions for a 150 mg capsule formulation made using Example 1 described herein and one taught in the prior art based on extrusion spheronization; U.S. Patent No. 6,274,171. These embodiments show the presence of a lag phase/time in the capsule of the present invention in comparison to the high rate of input and the sharper peak demonstrated by the prior art.

Method for Making the Extended Release Composition

The venlafaxine ingredient and at least one component that acts as both a diluent and a compression aid, and at least one glidant are blended and granulated in a solvent, such as water. The wet granules are dried and milled with at least one lubricant. The lubricated granules were blended and compressed into a core of a suitable size.

The core can be made, for example, using wet granulation techniques and by direct compression or use of roller compaction techniques.

A coating composition of at least one water soluble gellable polymer and at least one water insoluble organosoluble polymer is blended in a solvent and applied to the core providing an extended release coated compressed core. These coated cores can be encapsulated, as described above, to provide an extended release capsule, a sachet, to form a tablet, and/or a caplet.

Encapsulated extended release compositions may be produced in a uniform dosage for a specified dissolution profile and therapeutics end point upon oral administration by techniques understood in the art. For instance, the core components may be blended for uniformity with a desired concentration of active ingredient, in a high shear granulator and then granulated with a solvent and dried in a tray dryer oven or a fluid bed dryer. The resulting granules are milled in a co-mill, discharged and admixed with magnesium stearate in a v-blender to obtain a batch of uniform blend. The resulting blended granules are pressed into tablets of 2 to 3 mm diameter and height in a rotary tablet press. The tablets are coated in a side vented perforated tablet coater or in fluid bed coater.

The terms "extended release" and "controlled release" referred to herein are defined for purposes of the present invention as the release of the drug from the dosage form at such a rate that when a dose of the drug is administered in the extended release or controlled-release form, blood (e.g., plasma) concentrations (levels) of the drug are maintained within the therapeutic range but below toxic levels over a selected period of time.

When introducing elements disclosed herein, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements unless the context dictates otherwise. For example, the term "a compound" and "at least one compound" may include a plurality of compounds, including mixtures thereof. The terms "comprising", "having", "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.

The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. The Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation. Examples

Example 1: Venlafaxine Hydrochloride Extended Release Capsules

(1 ) Manufacture of a Tablet Core

Water*

*10-20 wt% of water is used for granulation

The venlafaxine HCI, lactose, microcrystalline cellulose, and silicon dioxide were blended in a Robocop high shear granulator using a rotor speed of about 1500 rpm for about 5 minutes. The mixture was granulated with water for about 2 minutes with the rotor speed set at about 1500 rpm. The wet granules were discharged and dried in a fluid bed dryer to an LOD of less than about 2 wt%. The dried granules are passed through a co-mill with a sieve size of about 1 mm. The milled granules were lubricated by charging a v-blender with the milled granules and adding magnesium stearate. The lubricated granules were blended for about 5 minutes. The lubricated granules were fed into a rotary tablet press and tablets were compressed to a diameter of about 3mm.

(2) Coating of the Tablet Core and Manufacture of an Extended Release Tablet

Using a high shear mixer, about 45 g of ethyl cellulose, about 20 g of hydroxypropylmethylcellulose, about 10.8 g of talc, and about 5.4 g of dibutyl sebacate are mixed in 485 g of ethanol to form a solution of the coating composition.

The coating composition was applied to 900 g of a bed of the uncoated tablet cores in a tablet coater to obtain an extended release coated tablet having a coating weight gain of about 5 wt%.

These coated tablets were filled into pharmaceutically acceptable capsules (e.g. starch, hydroxypropylmethyl cellulose or gelatin capsules).

Example 2 Same as Example 1 except that lactose and microcrystalline cellulose are replaced with 33 wt% mannitol.

Example 3

Same as Example 1 except that the coating composition is applied to the tablet core to obtain a coating weight gain of about 3 wt%.

Example 4

Same as Example 1 except that the coating composition is applied to the tablet core to obtain a coating weight gain of about 10 wt%.

Example 5: Venlafaxine Hydrochloride Extended Release Capsules

(1 ) Manufacture of a Tablet Core

^*10-20% (w/w) of water is used for granulation The venlafaxine HCI, lactose, and silicon dioxide were blended in a Robocop high shear granulator using a rotor speed of about 1500 rpm for about 5 minutes. The mixture was granulated with water for about 2 minutes with the rotor speed set at about 1500 rpm. The wet granules were discharged and dried in a fluid bed dryer to an LOD of less than about 2 wt%. The dried granules are passed through a co-mill with a sieve size of about 1 mm. The milled granules were lubricated by charging a v-blender with the milled granules and adding magnesium stearate. The lubricated granules were blended for about 5 minutes. The lubricated granules were fed into a rotary tablet press and tablets were compressed to a diameter of about 3mm.

(2) Coating of the Tablet Core and Manufacture of an Extended Release

Tablet

Using a high shear mixer, about 50 g of ethyl cellulose, about 31 g of hydroxypropylmethylcellulose, 15.3 g talc, and about 7.5 g of dibutyl sebacate are mixed in 677 g of ethanol to form a solution of the coating composition. The coating composition was applied to 900 g of a bed of the uncoated tablet cores in a tablet coater to obtain an extended release coated tablet having a coating weight gain of about 5 wt%. These coated tablets were filled into pharmaceutically acceptable capsules (e.g. starch, hydroxypropylmethyl cellulose or gelatin capsules).

Claims

WHAT IS CLAIMED IS:

1. An extended release composition comprising a coated compressed core having a core and a coating composition, (i) the compressed core comprising: at least about 45 wt% of a venlafaxine ingredient; less than about 50 wt% of at least one component that acts as both a diluent and a compression aid; less than about 10 wt% of at least one glidant; and less than about 10 wt% of at least one lubricant; and

(ii) the coating composition comprising: at least one water soluble gellable polymer; and at least one water insoluble organosoluble polymer.

2. The extended release composition of claim 1 , wherein the venlafaxine ingredient is from about 45 wt% to about 95 wt%.

3. The extended release composition of claim 2, wherein the venlafaxine ingredient is from about 50 wt% to about 95 wt%; about 55 wt% to about 95 wt%; about 60 wt% to about 90 wt%; about 60 wt% to about 80 wt%; or from about 65 wt% to about 80 wt%.

4. The extended release composition of any one of claims 1 to 3, wherein said at least one component is from about 5 wt% to about 45 wt%; from about 5 wt% to about 35 wl%; from about 10 wt% to about 35 wt%; from about 15 wt% to about 35 wt%; or from about 25 wt% to about 35 wt%.

5. The extended release composition of any one of claims 1 to 4, wherein said at least one glidant is from about 0.5 wt% to about 5 wt%; from about 0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%.

6. The extended release composition of any one of claims 1 to 4, wherein said at least one lubricant is from about 0.5 wt% to about 5 wt%; from about

0.5 wt% to about 4 wt%; from about 0.5 wt% to about 3 wt%; from about 0.5 wt% to about 2 wt%; or from about 1 wt% to about 2 wt%.

7. The extended release composition of any one of claims 1 to 6, wherein the coating composition has less than about 60 wt% of said at least one water soluble gellable polymer and less than about 75 wt% of said at least one water insoluble organosoluble polymer.

8. The extended release composition of any one of claims 1 to 7, wherein a ratio of said at least one water soluble gellable polymer to said at least one water insoluble organosoluble polymer in the coating is from about 24:76 to about 76:24 or from about 30:70 to about 40:60.

9. The extended release composition of any one of claims 1 to 8, wherein said at least one water soluble gellable polymer is from about 5 wt% to about

55 wt%; from about 10 wt% to about 55 wt%; from about 15 wt% to about 55 wt%; from about 10 wt% to about 35 wt%; or from about 15 wt% to about 35 wt%.

10. The extended release composition of any one of claims 1 to 9, wherein said at least at least one water insoluble organosoluble polymer is from about 20 wt% to about 73 wt%; from about 35 wt% to about 65 wt%; from about 30 wt% to about 50 wt%; from about 30 wt% to about 45 wt%; from about 40 wt% to about 50 wt%.

11. The extended release composition of any one of claims 1 to 10, wherein said at least at least one water soluble gellable polymer is from about 15 wt% to about 55 wt% and said at least at least one water insoluble organosoluble polymer is from about 35 wt% to about 73 wt%.

12. The extended release composition of any one of claims 1 to 11 , wherein the core is coated with of from about 0.1 wt% to about 50 wt% of the coating composition.

13. The extended release composition of any one of claims 1 to 12, wherein the core is coated with of from about 1 wt% to about 20 wt%, from about 1 wt% to about 10 wt%, from about 1 wt% to about 7 wt%, from about 3.5 wt% to about 7 wt%, from about 3.5 wt% to about 6 wt%, or from about 4 wt% to about 5 wt%.

14. The extended release composition of any one of claims 1 to 13, wherein the coating composition is applied to the core to yield a surface area of less than about 100 mg/cm².

15. The extended release composition of any one of claims 1 to 14, wherein the core is free of water soluble or water insoluble cellulose ether.

16. The extended release composition of any one of claims 1 to 15, wherein the coating composition further comprises a plasticizer and an anti- tacking agent.

17. The extended release composition of any one of claims 1 to 16, wherein said at least one anti-tacking agent is from about 10 wt% to about 80 wt% and at least one plasticizer is from about 10 wt% to about 80 wt%.

18. The extended release composition of any one of claims 1 to 17, wherein the venlafaxine ingredient comprises venlafaxine and/or at least one pharmaceutically acceptable salt thereof.

19. The extended release composition of any one of claims 1 to 18, wherein said at least one component that acts as both a diluent and a compression aid comprises microcrystalline cellulose, calcium phosphate, mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol; arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, and/or raffinose.

20. The extended release composition of claim 19, wherein said at least one component that acts as both a diluent and a compression aid comprises microcrystalline cellulose, lactose, mannitol, calcium phosphate and/or sorbitol.

21. The extended release composition of any one of claims 1 to 20, wherein said at least one glidant comprises silicon dioxide, starch, calcium silicate, Cabosil, Syloid, and/or silicon dioxide aerogel.

22. The extended release composition of claim 21 , wherein said at least one glidant comprises silicon dioxide.

23. The extended release composition of any one of claims 1 to 22, wherein said at least one lubricant comprises alkali stearate, polyethylene glycol, adipic acid, hydrogenated vegetable oil, sodium chloride, sterotex, glycerol monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil, and/or waxy fatty acid ester.

24. The extended release composition of any one of claims 1 to 23, wherein said at least one lubricant comprises magnesium stearate, talc and/or glycerol monostearate.

25. The extended release composition of any one of claims 1 to 24, wherein said at least one water soluble gellable polymer comprises swellable, gellable cellulose ether, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, copolyvidone, polyvinyl pyrrolidone, polyethylene glycol, and hydroxyethyl cellulose, polyol, carbomers, carboxymethyl cellulose, polysaccharide gum, and/or polyethylene oxide.

26. The extended release composition of claim 25, wherein said at least one water soluble gellable polymer comprises hydroxypropylmethyl cellulose.

27. The extended release composition of any one of claims 1 to 26, wherein said at least one water insoluble organosoluble polymer comprises polyvinyl acetate, eudragit, cellulose derivative, ethyl cellulose, cellulose acetate and/or plasticizer.

28. The extended release composition of claim 27, wherein said at least one water soluble gellable polymer comprises ethyl cellulose.

29. The extended release composition of any one of claims 1 to 28, wherein said at least one component comprises microcrystalline cellulose and at least one of lactose, mannitol and/or sorbitol; said at least one glidant comprises silicon dioxide and said at least one lubricant comprises magnesium stearate.

30. The extended release composition of any one of claims 1 to 28, wherein said at least one component comprises at least one of lactose, mannitol and/or sorbitol; said at least one glidant comprises silicon dioxide and said at least one lubricant comprises magnesium stearate.

31. The extended release composition of any one of claims 1 to 28, wherein said at least one component comprises from about 10 wt% to about 30 wt% microcrystalline cellulose and from about 5 wt% to about 20 wt% lactose; said at least one glidant comprises less than about 10 wt% of silicon dioxide and said at least one lubricant comprises less than about 10 wt% magnesium stearate.

32. The extended release composition of any one of claims 1 to 28, wherein said at least one component comprises from about 10 wt% to about 25 wt% microcrystalline cellulose and from about 5 wt% to about 15 wt% lactose; said at least one glidant comprises less than about 10 wt% of silicon dioxide; and said at least one lubricant comprises less than about 10 wt% magnesium stearate.

33. The extended release composition of any one of claims 1 to 28, wherein said at least one component comprises from about 15 wt% to about 25 wt% microcrystalline cellulose and from about 10 wt% to about 15 wt% lactose; said at least one glidant comprises from about 0.5 wt% to about 3 wt% silicon dioxide, and said at least one lubricant comprises from about 0.5 wt% to about 3 wt% magnesium stearate.

34. The extended release composition of any one of claims 1 to 33, wherein the coated core is a tablet, pellet, mini-tablet, and/or caplet.

35. The extended release composition of any one of claims 1 to 34, wherein the coated compressed core is a plurality of coated cores.

36. The extended release composition of claim 35, wherein the plurality of coated cores are encapsulated.

37. The extended release composition of any one of claims 1 to 36, wherein the coated compressed core is a plurality of coated cores in a capsule and/or sachet.

38. The extended release composition of any one of claims 1 to 37, wherein the extended release composition provides a therapeutic blood serum level over a twelve or twenty four hour period that are capable of demonstrating a lag time and/or lag phase during drug release in-vivo.

39. A method for administering the extended release composition of any one of claims 1 to 38 to a mammal in need of treatment for depression, panic disorder, anxiety disorder and/or social phobias.

40. Use of the extended release composition of any one of claims 1 to 38 in a medicament for the treatment of depression, panic disorder, anxiety disorder and/or social phobias.

41. Use of the extended release composition of any one of claims 1 to 38 for the treatment of depression, panic disorder, anxiety disorder and/or social phobias.

42. A method for providing a therapeutic blood plasma concentration of the venlafaxine ingredient over a twelve or twenty four hour period with diminished incidences of nausea and emesis which comprises administering orally to a patient in need thereof an extended release composition of any one of claims 1 to 38, with or without a lag time, to provide a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

43. A method for providing a therapeutic blood plasma concentration of the venlafaxine ingredient over a twelve or twenty four hour period with diminished incidences of nausea and emesis which comprises administering orally to a patient in need thereof an extended release composition of any one of claims 1 to 38 that after a lag time provides a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

44. A method for substantially eliminating the troughs and peaks of drug concentration in a patients blood plasma attributed to the therapeutic metabolism of plural daily doses of the venlafaxine ingredient which comprises administering orally to a patient in need thereof, an extended release composition of any one of claims 1 to 38, with or without a lag time, to provide a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

45. A method for substantially eliminating the troughs and peaks of drug concentration in a patients blood plasma attributed to the therapeutic metabolism of plural daily doses of the venlafaxine ingredient which comprises administering orally to a patient in need thereof, an extended release composition of any one of claims 1 to 38, that after a lag time provides a peak blood plasma level of the venlafaxine ingredient of from about 1 to about 18 hours.

46. A method for making the extended release composition of any one of claims 1 to 33, the method comprising: combining the venlafaxine ingredient, said at least one component, and said at least one glidant and granulating in a solvent to provide granules; combining the granules with said at least one lubricant to provide lubricated granules; compressing said lubricated granules into the core; and coating the core with the coating composition.

47. The method of claim 46, wherein said combining the venlafaxine ingredient, said at least one component, and said at least one glidant and granulating in a solvent to provide granules comprises combining the venlafaxine ingredient, said at least one component, and said at least one glidant in a high shear granulator and granulating with said solvent.

48. The method of claim 46 or 47, wherein the granules are dried.

49. The method of claim 48, wherein the granules are dried in a tray dryer oven or a fluid bed dryer.

50. The method of any one of claims 47 to 49, wherein the granules are milled and admixed with said at least one lubricant to provide lubricated granules.

51. The method of any one of claims 47 to 50, wherein the core is coated in a side vented perforated tablet coater or in fluid bed coater.

52. The method of any one of claims 47 to 51 , wherein the coated core is a tablet, pellet, mini-tablet, and/or caplet.

53. The method of any one of claims 47 to 52, wherein the coated core is a plurality of coated cores.

54. The method of claim 53, wherein the plurality of coated cores are encapsulated.

55. The method of any one of claims 1 to 36, further comprising combining the plurality of coated cores into a capsule, tablet, caplet and/or a sachet.